5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one (Compound I) is a potent β2 adrenoceptor agonist first disclosed in WO 2006/122788. This compound has the following chemical formula.

Crystalline naphthalene-1,5-disulfonic acid salts (heminapadisylates) of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one have been described in WO 2008/095720. The crystalline heminapadisylate salt of compound (I) (hereinafter, called type α polymorph) is identified by the X-Ray Powder Diffraction, DSC pattern and TGA pattern. This compound has the following chemical formula.

WO 2010/102831 describes an improved process for preparing the heminapadisylate salt of compound of formula (I). In particular the heminapadisylate salt is obtained in a one pot reaction without isolating said compound of formula (I). Once the hydrogenation process of 8-(benzyloxy)-5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)-hexyl]amino}-1-hydroxyethyl)quinolin-2(1H)-one is completed and the catalyst is removed from the reaction mixture, a solution of naphthalene-1,5-disulfonic acid tetrahydrate in methanol/acetic acid (2:1) is added to the reaction mixture. This process results in formation of the type α polymorph previously disclosed in WO 2008/095720.
This compound as a potent β2 adrenergic receptor agonists is advantageously administered directly into the respiratory tract by inhalation when used for treating pulmonary or respiratory disorders. Several types of pharmaceutical inhalation devices have been developed for administering therapeutic agents by inhalation including dry powder inhalers (DPI), metered-dose inhalers (MDI) and nebulizer inhalers.
Dry powder inhalers are well known devices for administering pharmaceutically active agents to the respiratory tract. They are particularly suitable when used for the administration of active agents in the treatment of respiratory diseases such as asthma, COPD, emphysema or the like. Since the drug acts directly on the target organ, smaller quantities of the active ingredient should be used.
Dry powder formulations typically comprise a pharmaceutically active agent and an excess of a pharmaceutically acceptable excipient or carrier. The efficacy of a dry powder inhaler is related to the extent of the drug deposition in the lungs, which in turn depends on the drug formulation and the device being used. In order to be able to reach the lower respiratory airways, the drug needs to be delivered in finely divided particles, with an aerodynamic diameter of less than 5 μm.
The Fine Particle Dose (FPD) of a drug from a dry powder inhaler is a measure of the quantity of drug of effectively deliverable particle size (i.e. with an aerodynamic diameter no greater than 5 μm) emitted after a single actuation of the DPI. The Fine Particle Fraction (FPF) is the percentage (%) of the emitted dose that the FPD represents. A high FPF is clearly desirable as more of the administered drug will be able to reach the lungs where it can be effective and thus less amount of drug will be required to achieve the optimum dose of the drug.
The use of an additive material to improve the Fine Particle Fraction (FPF) has been extensively used in a dry powder formulation. It was first mentioned in a PCT application No. WO 87/05213 where the preparation of an excipient (lactose) containing a lubricant, such as magnesium stearate or sodium benzoate, was described.
WO 96/23485 describes the preparation of a dry powder formulation containing additive materials selected from amino acids, phospholipids or surfactants in order to promote the release of the small particles of active ingredient leading to an increase in the Fine Particle Fraction (FPF).
U.S. Pat. No. 6,645,466 describes the use of magnesium stearate in dry powder formulations for inhalation with the purpose of improving the dry powder formulation stability with regard to moisture and thereby maintaining the FPF when the formulation is tested at higher relative humidity.
WO 2005/041922 describes the use of a physiologically acceptable metal phosphate salt, such as dibasic calcium phosphate, instead of magnesium stearate, in dry powder formulations thus improving the FPF.
WO 2009/061273 describes dry powder formulations containing certain ascorbic acid derivatives. It is stated that the presence of this additive material shows good inhalation performance by increasing the FPF.
Although the problem to increase the FPF is apparently solved by means of addition of certain additive materials to the formulation, it is well known in the art that adding further ingredients to a pharmaceutical formulation leads to a greater complexity in terms of manufacturing process. For instance, some mixing problems have been described for ternary mixtures, such as agglomeration, segregation or drug uniformity issues, especially when a fine excipient is added to the drug, due to a lower adhesion to the surface of the coarse carrier particles. Moreover, additional development studies may be required in order to achieve the regulatory approval of a new ingredient for inhalation administration.
It has been surprisingly found that new polymorphic crystal forms of the heminapadisylate salt of compound I exhibit a higher Fine Particle Fraction (FPF) than the standard Type α polymorph, while maintaining the crystallinity, non hygroscopicity and stability properties. The good inhalation performance of the new polymorphic crystal forms in a dry powder formulation is enhanced without the presence of any further additive material.